The role of Thyrotropin Releasing Hormone (TRH) in extra hypothalamic areas of the central nervous system(CNS) is unclear but has been thought to act as a neurotransmitter or neuromodulater in these locations. It has been recognized that various neural peptides, including substance P (SP), may function as neurotropic factors. Recently, our laboratory reported (in abstract) that transfection of fetal rat hypothalamic cultures with an adenovirus containing an antisense rat TRH cDNA led to neuronal cell death. This finding raises the possibility that TRH may function not only as an hypothalamic releasing factor but also as a neurotrophic factor in CNS. A number of neurotrophins (or factors that preserve neuronal integrity) have been described in the CNS including brain-derived neurotrophic factor (BDNF) which has been reported to be colocalized with TRH. Accordingly we speculate that TRH and BDNF may cooperate as neurotrophic factors (or as inhibitor of apoptosis) in the CNS. There is also evidence that BDNF interacts with the bcl-2 family of protooncogenes in regulating the apoptotic process. A possible mechanism through which a TRH "knockout" could induce neuronal death is that TRH may cooperate with BDNF to influence the apoptosis, either as an inhibitor of the apoptosis process or as a bcl-2 activator to stimulate bcl-2 to prevent cell death. This proposal is designed to test the hypothesis that TRH is a neurotrophic factor necessary for the maintenance of neurons in the CNS and that it cooperates with BDNF through the Bcl-2 family of protooncogenes in the process of neuronal apoptosis. These studies may have relevance to the pathogenesis of degenerative neurologic disorders such as Alzheimer's disease or Parkinson's disease as well as normal gaining.